Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease, is a fatal neurodegenerative disease resulting from the destruction of motor neurons in the spinal cord, brainstem and cortex that are responsible for voluntary movement. This disease clinically manifests as progressive muscular weakness and atrophy, leading to paralysis and death within 3-5 years of disease onset.
Approximately 20,000 people in the United States have ALS, and 5,000 people are diagnosed with ALS each year. ALS is common worldwide, affecting people of all races and ethnic backgrounds. The average age of onset of ALS is between 40 and 60 years of age, but ALS can strike both younger and older men and women. In 90-95% of ALS cases, the disease is apparently random (known as sporadic ALS (sALS)). In such SALS cases, there is no family history of the disease and no clearly associated risk factors. In 5-10% of ALS cases there is an inherited genetic link (known as familial ALS (fALS)).
Among the mutations associated with ALS, those in the Copper-Zinc superoxide dismutase (SOD1) gene have long been thought to cause the ALS disease through a toxic gain of function rather than impairment of the antioxidant function of the SOD1 enzyme. Other genes with mutations associated with the fALS include alsin (ALS2), senataxin (ALS4), vesicle associated membrane protein (VAPB, ALS8), Angiogenin and the p150 subunit of dynactin (DCTN1). Recently, more than thirty mutations in the TDP-43-coding region of Tardbp have been identified in ALS patients with or without apparent family history, corresponding to approximately 4% of fALS and less than 1% of sALS. Most patients with TDP-43 mutation(s) develop a classical ALS phenotype without cognitive deficit suggesting an important role of TDP-43 in the development of ALS. Additionally, expanded GGGGCC hexanucleotide repeats in the promoter of the C9ORF72 gene and appear as a very common cause of fALS and sALS, as well as ALS associated frontotemporal dementia (ALS-FTD).
Several mouse models have been established for ALS disease, which include strains of rodents having mutations in SOD1, TDP43, or FUS, ALS2-knockout mice, and mice with genetically engineered genes coding for the neurofilament subunits. Among these, the human mutant SOD1 (mSOD1) transgenic mouse model is currently the most widely used one because it shares several clinical phenotypes with ALS patients. The first symptom of mSOD1 mice is a fine “jittering/tremor” in one or more of the limbs, which appears at approximately 90 to 100 days of age. At later stages, the mice begin a clinical course, first with muscle weakness and/or paresis in the hind limbs, followed by ascent of paresis to the forelimbs and finally severe quadriplegia. None of the current animal models, however, translate to human disease in that the animals do not exhibit upper motor neuron symptoms, TDP43 and/or SOD1 aggregates, and/or non-motor neuron loss. Accordingly, an animal model that more closely reflects ALS in humans is needed.